1. Field of the Invention
This invention relates to a process for preparing a bioresorbable hemostat by treating oxidized cellulose with calcium or a combination of calcium and sodium or potassium.
2. Description of the Related Art
Oxidized cellulose fabrics are bioresorbable and absorbent fabrics that have long been used in medical applications. Both naturally-occurring and regenerated cellulose can be oxidized. For convenience and brevity, we refer to both as "oxidized cellulose." Three examples of such a fabric are Interceed* (TC7) Absorbable Adhesion Barrier, Surgicel* Absorbable Hemostat and Surgicel Nu-Knit* Absorbable Hemostat (all available from Johnson & Johnson Medical, Inc., Arlington, Tex.). However, all these materials are acidic. The pH of the aqueous phase of 1 g of Interceed Barrier suspended in 100 ml of purified water is approximately 4.1. The surface pH of a fully water-saturated piece of fabric is about 1.7. Materials such as thrombin, tissue plasminogen activator analogue (t-PAA), and other highly acid-sensitive materials are inactivated immediately on such matrices, precluding their use for delivery of these materials to a surgical site. Alternatively, if such a material is to be delivered on an oxidized cellulose fabric, the fabric must first be neutralized. Thus, past efforts to modify oxidized cellulose in order to improve its properties have generally focused on neutralizing the material.
Doub et al., in U.S. Pat. No. 2,517,772, describe the impregnation of neutralized oxidized cellulose products with thrombin. They disclose a method of neutralizing oxidized cellulose cloth with an aqueous sodium bicarbonate solution (Example 2) or an aqueous calcium acetate solution (Example 1). Example 2 of the Doub et al. patent discloses neutralizing oxidized cellulose gauze with an aqueous solution of strongly basic sodium bicarbonate and then impregnating the neutralized product with thrombin. The thrombin impregnated gauze is then frozen and dried from the frozen state to provide a highly hemostatic surgical dressing. The patent does not disclose any practical data pertaining to testing in animals.
Dol'berg et al., Farm Zh. (Kiev) 1971,26(2),53-56, studied the hemostatic properties of oxidized cellulose and combined the material with various pharmaceutical compounds. They report that the sodium and potassium salts of oxidized cellulose can be used in medicine and that the potassium salt has advantages over the acid form, in that it is neutral and is compatible with many pharmaceutical substances.
Barinka et al., in British Patent Specification 1,593,513, published Jul. 15, 1981, disclose a process for oxidizing cellulose with a mixture of nitric acid and stabilized ("phlegmatized") sodium nitrate. The material is then stabilized with an aqueous-alcoholic solution of urea or its N, N-disubstituted alkyl or acyl derivatives. Finally, the oxidized cellulose is converted to its calcium, sodium, or ammonium salt by repeatedly alternating absorption-in and centrifuging-off a solution of an equimolar mixture of chloride and acetate of calcium, sodium, or ammonium.
Saferstein et al., in U.S. Pat. No. 5,134,229, disclose a process for preparing storage stable oxidized cellulose by contacting an acidic oxidized cellulose material with a water and alcohol solution of a slightly basic salt of a weak acid to elevate the pH of the cellulose material to between 5 and 8. Their salt of a weak acid is preferably selected from among sodium acetate, potassium acetate, sodium citrate, sodium formate, potassium citrate, potassium formate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, or mixtures thereof. Repeating the processes of Doub et al., they found that neutralizing oxidized cellulose cloth in aqueous solutions of sodium bicarbonate results in a cloth that is partially gelled, distorted from its original size, and very weak, with little integrity. The tensile strength of the cloth is too low for practical use such as, for example, a hemostat. Completely neutralizing oxidized cellulose cloth with calcium acetate in accordance with the teachings of Example 1 of the Doub et al. patent, they found, provides a cloth that is of acceptable integrity but is irritating to mammalian skin and other body cells at the point of contact. Further, large, whitish masses presumed to be granuloma tissue forms at the application site of the cloth. Apparently, such tissue is attempting to encapsulate the calcium salt of the oxidized cellulose cloth. Saferstein et al. do not disclose a calcium salt as an option for neutralizing oxidized cellulose.
The role of calcium in hemostasis is well known; in fact, the International Committee on Nomenclature of Blood Clotting Factors has designated calcium as one of 13 blood-coagulation factors (Factor IV). Calcium plays an important role in the conversion of protothrombin to thrombin, one of the stages of the blood coagulation process. Details of the hemostasis process appear in standard medical texts, such as Remington's Pharmaceutical Sciences, ed. by A. R. Gennaro (Mack, Easton, Pa., 1990). There are also examples of the practical application of calcium to enhance hemostasis. Superstat* absorbable collagen hemostat contains calcium ions to enhance its hemostatic efficacy. On the other hand, to prevent blood from coagulating inadvertently, citric acid is added to blood collection bags to sequester the calcium in blood serum.
Despite the recognized value of neutralized oxidized cellulose as a hemostatic material and the important role that calcium plays in hemostasis, the goal of an absorbable calcium-modified hemostat had not been realized before the present invention.